Reduced blockade by extracellular Mg(2+) is permissive to NMDA receptor activation in cerebellar granule neurons that model a migratory phenotype.
Reduced blockade by extracellular Mg(2+) is permissive to NMDA receptor activation in cerebellar granule neurons that model a migratory phenotype.
复制标题
细胞外 Mg(2 ) 的阻断减少，允许模拟迁移表型的小脑颗粒神经元中 NMDA 受体激活。
DOI：
10.1111/j.1471-4159.2010.06746.x
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发表时间：
2010
影响因子：
4.7
通讯作者：
Vallano,MaryLou
中科院分区：
文献类型：
--
作者：
Gerber,AdamM;Beaman-Hall,CarolM;Mathur,Anjili;Vallano,MaryLou
神经化学杂志。（2010）114，191- 202.摘要NMDA受体（NMDAR）有助于整个CNS的神经元发育。然而，它们在突触成熟之前的激活模式尚不清楚，因为它们不与α-氨基-3-羟基-5-甲基异恶唑-4-丙酸酯受体（AMPAR）共定位，AMPAR通常提供足够的去极化以缓解Mg 2+的电压依赖性阻断。我们使用在接近生理KCl浓度下培养的小脑颗粒神经元（CGN）来检查NMDAR反应的成熟依赖性变化。相反，大多数研究使用KCl补充培养基来促进存活。第2-4 天，体外CGN：（i）表达类似于活体迁移表型的发育标志物;（ii）维持钙响应元件结合蛋白磷酸化的基础量，这需要NMDAR和钙/钙调蛋白依赖性激酶，但不需要AMPARs;（iii）表现出NMDA介导的Ca 2+内流，不被环境Mg 2+（0.75 mM）或AMPARs有效阻断;（iv）与突触连接的CGN相比，维持更多去极化的静息膜电位和增加的阻力。此外，外植体培养物中迁移的CGN表明NMDA介导的Ca 2+内流不能被0.75 mM Mg 2+有效阻断，并且NMDAR而不是AMPAR拮抗剂减缓迁移。 这些数据表明，未成熟CGN的生物物理特性使得NMDAR对Mg 2+阻断不太敏感，从而在不存在AMPAR去极化的情况下增强激活的可能性。
J. Neurochem.(2010)114, 191–202.AbstractNMDA receptors (NMDAR) contribute to neuronal development throughout the CNS. However, their mode(s) of activation preceding synaptic maturation is unclear, as they are not co‐localized with alpha‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptors (AMPARs) which normally provide sufficient depolarization to relieve voltage‐dependent blockade by Mg2+. We used cerebellar granule neurons (CGNs) cultured at a near‐physiological KCl concentration to examine maturation‐dependent changes in NMDAR responses. In contrast, most studies use KCl‐supplemented medium to promote survival. At 2–4 daysin vitroCGNs: (i) express developmental markers resembling thein vivomigratory phenotype; (ii) maintain a basal amount of calcium responsive element‐binding protein phosphorylation that requires NMDARs and calcium/calmodulin‐dependent kinases, but not AMPARs; (iii) exhibit NMDA‐mediated Ca2+influx not effectively blocked by ambient Mg2+(0.75 mM) or AMPARs; (iv) maintain a more depolarized resting membrane potential and increased resistance compared to synaptically‐connected CGNs. Moreover, migrating CGNs in explant cultures demonstrate NMDA‐mediated Ca2+influx not effectively blocked by 0.75 mM Mg2+, and NMDAR but not AMPAR antagonists slow migration. These data suggest the biophysical properties of immature CGNs render NMDARs less sensitive to Mg2+blockade, enhancing the likelihood of activation in the absence of AMPAR depolarization.